Process for preparing sulfathiazole



Patented Apr. 15, 1 952 A UNITED STATES PATENT .OFF

PROCESS FOR PREPARING SULFATHIAZOLE Thomas F. Cleary, Jr., New Brunswick, N. as-

signor to E. R. Squibb ,8; Sons, New York, N. Y., a corporation of New York No Drawing. Original application June 29, 1946,

Serial No. 680,513. Divided and this application August12, 1950, Serial No. 179,371

V This application is a division of application Serial No. 680,513, filed June 29, 194.6.

This invention relates to the production of sulfathiazole.

Prior to this invention, sulfathiazole was generally prepared by condensing one mol of p-acetamino-benzenesulfonyl chloride with one mol of and (under proper conditions) sodium hydroxide and magnesium hydroxide. V j

Other salting-out salts may be used in place of sodium chloride to produce a twoephase me- Z-amino-thiazole in the presence of pyridine, and deacetylating the resulting N' -acetyl-sulfathiazole, a high degree of dryness being essential for the condensation.

Also, prior to this invention, sulfathiazole had been prepared by condensing two mols of p-acetamino-benzenesulfonyl chloride with one mol of 2-amino-thiazole to produce a bis compound-- 1. e., the di-(p-acetamino-benzenesulfonyl) derivative of 2-amino-thiazole, or bis-N-(p-acetamino-benzenesulfonyl) 2-amino-thiazole-and hydrolyzing it to suliathiazole (cf. application Serial No. 334,990, filed May 13, 1940, which was vested in the Alien Property Custodian and published April 20, 1943). Although such process employs an additional mol of p-acetamino-ben zenesulfonyl chloride, that disadvantage is partially offset when the reactants are employed in the wet state (dryness not being essential for the condensation). Such Wet process, however,

gives relatively low yields of the bis" compound (and consequently low overall yields of sulfathiazole).

It is the object of this invention to provide: [A] an advantageous method of preparing sulfathiazole; [B] an improved method of preparing jg di-(p-R-benzenesulfonyl) derivatives of 2-amino-thiazole, R-representing a substituent capable of conversion into an amino group-especially the di-(p-acetamino-benzenesulfonyl) derivative of 2-amino-thiazole; and [C] anadvantageous method of converting di-(p-R-benzenesulfonyl) derivatives of 2-amino-thiazoleespecially the di-(p-acetamino-benzenesulfonyl) derivative of Z-amino-thiazole-into sulfathiazole.

In the practice of this invention, a di-(p-R- benzenesulfonyl) derivative of 2-amino-thiazole is prepared by reacting the p-R-benzenesulfonyl halide with 2-amino-thiazole in the presence of an acid-binding agent, in a two-phase medium of water and an inert organic solvent iorthe reactants, inter alia, ether, ethylene dichloride, pyridine, acetone, and mixtures thereof. Preferably, the inert organic solvent is acetone; the two-phase acetone-water medium being formed by substantially saturating the water with salt (sodium chloride).

The utilizable acid-binding agents (or acidacceptors) comprise, inter alia, sodium bicarbonate (which is preferred), ammonium hydroxide,

sodium carbonate, pyridine. 'dimethyl-aniline,

, sulfonhalide.

dium, inter alia, ammonium sulfate, sodium sulfate, and other alkali (including alkaline-earthmetal and ammonium) halides.

Desirably, the amount of sulfonhalide (i; e. p- R-benzenesulfonyl halide) used is in slight excess over the ratio of 2 mols of the sulfonhalide to 1 mol of Z-amino-thiazole; the amount of water used is the minimum required to obtain workable fluidity in the reaction. mixture; the amountof salting-out salt used is substantially that required to saturate the amount of water used: and the amount of acid-binding'agentused is that thee retically required, i. e., 1 mol per molof'the The di-(p-R-benzenesulionyl) derivative of 2-5 amino-thiazole obtained may then be subjected to (alkaline or acid) hydrolysis to split off enact the p-R-benzenesulfonyl groups and obtain the desired 2- (p R. benzenesulfonamido) -thiazole.

-- R-benzenesulfonamido)--thiazole; and where different, these sulfonamides may be separately recovered. I

Among the'basic organic amines utilizable in the practice'of this invention are guanidine and homosulfanilamide. Desirably, the di-(p-R-'- benzenesulfonyl) derivative of 2-amino -thiazole is hydrolyzed with an aqueous solution of a member of the group consisting of ammonia and guanidine, to obtain p-R-benzenesulfonamide and N- (p-R-benzenesulfonyl) -guanidine, respectively, concurrently with the readily separable 2-(p-R-benzenesulfonamido)-thiazole.

Among the .substituents capable of conversion into an amino group (represented by R) are acylamino, nitro, azo, and halo; such substitue'ntfin I the final reaction product) being converted into an amino group in 'theconventional manner. Thus, where R in the reactant p-R-benzenesul- .fonylhalide is an acylaminogroup, the acylree action product obtained is deacylated;(or hydro ICE lyzed) in the conventional manner (e. g., by heating with sodium hydroxide solution); and when R in the reactant is nitro (i. c., the reactant is a p-nitro-benzenesulfonyl halide), the nitro reaction product obtained is converted into the corresponding amino compound in the usual manner (e. g., by reduction withiron and hydrochloric acid, or by hydrogenation inthe presence of a palladium catalyst).

The process of this invention is especially applicable to the production of sulfathiazole along with sulfanilamide or sulfaguanidine from a di (p-acylamino-benzenesulfonyl) derivative of 2- amino-thiazole. In such process, the sulfonamides formed may be separately recovered by cooling the reaction mixture, separating the precipitated N -acyl-sulfanilamide or N -acylsulfaguanidine, acidifying Tthe filtrate, and recovering the precipitated w -acyl-s'ulfathiazole.

,In the preparation of bis compounds in accordance with this invention, the reactants may be mixed in any order. Thus, all the reactants except the acid-binding agent may be mixed together first, and the acid-binding agent then added; or, preferably, all the reactants except the sulfonchloride are mixed together, and the sulfonchloride isthcn added as a wet cake or slurry. The ammonia employed for the hydrolysis of the bis compound is conveniently added as ammoni'a water. Alternatively, the ammonia may be added during the reaction (e. g., by passing ammonia into a heated and agitated aqueous suspension of the .bis compound; or the ammonia may be formed in situ (e. g., by the use of aqueous solutions of ammonia-yielding compounds, inter alia, ammonium carbonate, ammonium bicarbonate, and ammonium carbamate).

i The following examples are illustrativeoi the invention:

EXAMPLE 1 (a) A solution of 50 g. 2-amino-thiazole in 200 ml. (160 g.) acetone is added to a solution of 120 g. sodium chloride and 90 g. sodium bicarbonate in 400 ml. water; the temperature ofthe mixture is adjusted to 25-30 (3.; and 240 g. p-acetaminobenzenesulfonyl chloride is added to the mixture with good agitation as rapidly as foaming will permit, and stirring is continued until the evolution of G: has ceased and a smooth slurry (of the bis compoundyis obtained.

(b) To this slurry isadded 110 g. ammonia water (26-28%), and the mixture is agitated and maintained at 65 C. for 2.5 hours. The reaction mixture (a thin, amber-colored slurry of sandy crystals) is cooled to 20 C., and filtered. The separated crystals (of N -acetyl-sulfanilamide) are washed with two 50 cc. portions of cold water, and the washes are added to the mother liquor (filtrate). [The N' -acety'l-sulfanilamide obtained, when dry, melts at 214-216" (3., and weighs 102 g., representing 92% of the theoretical yield based on one-half of the sulfonchloride used] The mother liquor (containing the N -acetyl-sulfathiazole) is treated with g. Darco. (an activated charcoal) for one hour, and then filtered; and the pH of the filtrate is adjusted to 5.5 by addition of 38% hydrochloric acid (about 90 g. being required). The resulting precipitate (of N -acetyl-sulfathiazole) is filtered off, and washed with two 100 ml. portions of water. The dry, light-yellow productmelts at 250-254" C. and. weighs 130-135 g., representing 88 -9192. of the theoretical yield based on the 2- amino-thia'zole' used.

(c) 130 g. of the N -acetyl-sulfathiazole obtained is dissolved in a solution of 40 g. sodium hydroxide flakes in 200 ml. water, and the result ing clear, light-red solution is maintained at C. for about 2 hours. [It is necessary to determine with certainty that the deacetylation is complete, in order to avoid contamination of the sodium-sulfathiazole with N -acetyl-sulfathiaable; and the solution should therefore be maintained at 65 C. until no acid-insoluble matter remains, as'determine'd by the addition of a small sample of the reaction mixture to an excess of strong hydrochloric acid] When the deacetylation is complete, a solution of 50 g. sodium hydroxide flakes in ml. water is added, and the mixture is allowed to cool several hours to 20 C. The sodium-suliathiazole crystals formed are filtered ofi, washed free of dark mother liquor with two 50 ml. portions of 15% sodium chloride solution (the amount of sulfathiazole remaining in the mother liquor is negligible), and (if desired) converted into sulfathiazole in the usual manner (yield 89-91 g., representing -82% of the theoretical based on the N -acetyl-sulfathiazole used).

(d) 102 g. of the N -acetyl-sulfanilamide obtained is added to a mixture of 50 g. 34% hydrochloric acid and 300 ml. water, and the mixture is heated to boiling for 20 minutes, then treated with 2 g. Darco for 20 minutes, and filtered. The filtrate is neutralized to pH 4.5 with about 60 g. 32% sodium hydroxide solution, and cooled to 20 C.; and the resulting crude sulfanilamide crystals are filtered off, and washed with two 50 ml. portions of cold water. The product melts at 163-164 C. and weighs 77 g. (representing of the theoretical yield based on the N acetyl-sulfanilamide used). The crude sulfanilamide is further purified by dissolving it in 1 liter water by heating to 95 0., treating the solution with 1' g. Darco, filtering, cooling the filtrate to 15 C., filtering off the resulting sulfanilamide precipitate, washing it with two 50 ml. portions of cold distilled water, and drying. The sulfanilamide thus obtained melts at 164-166 C. and weighs 70g. (representing 75.5% of the theoretical yield from one-half of the sulfonchloride used).

EXAMPLE 2 (a) M ateridls 2-ami'no-thiazo1e (dried)-35 lbs.,assaying 94.4%

(0.33 mol) p Acetamino-benzenesulfonyl chloride165 lbs.,

assaying 95.5% (0.58 mol) Acetonelbs.

Sodium chloride-93 lbs.

Sodium bicarbonate-59 lbs. (0.070 mol) Water-264 lbs.

Procedure All materials except the sulfonchlorlde are mixed together in a '75-gallon glass-lined reactor equipped with an 80 R. P. M. anchor-type agitator, the sulfonchloride is added over a period'of one hour (while agitating). the rate of addition being governed by the foaming of the batch, and the reaction mixture is agitated for two hours after evolution of carbon dioxide has ceased. The resulting smooth slurry is centrifuged, and the separated bis compound is dried. It is light brown in color, melts at l23'-l2'5 C., 'and' weighs lbs. representing 97.5% of the theoretical yield) EThe bis compoundmay be purified by dissolving in" 6 parts warm acetone, adding an equal volume of water, and chilling, being thereby obtained as fine white needles melting with decomposition at 129-130 C.]

(b) Materials Pounds Procedure The bis compound, water, and hydrochloric acid are charged into a 75-gallon glass-lined reactor, and the mixture is heated with agitation to 98 C. (careful maintenance of the temperature below the boiling point being required to prevent serious foaming). After about 50 minutes, the reaction mixture becomes clear (indicating completion of the deacetylation); the Darco is then added, and the mixture is cooled to 50 C. and filtered through a rubber-covered filter press. [If considerable sulfathiazole hydrochloride has crystallized from the solution, it is necessary to re-slurry the press cake in water to recover it, or filter at a higher temperature] The filtrate (and washes) are adjusted to pH 6.5 by addition of the sodium hydroxide solution, and the crude suifathiazole precipitated is separated and dried. The product weighs 65 lbs. and assays 97.0% sulfathiazole (representing 76.2% of the theoretical yield based on the 2-aminothiazole).

(b, alternative.) The unisolated bis compound, i. e., the slurry obtained as described in section a, is converted into sulfathiazole (and sulfanilamide) by the procedure described in sections b and c of Example 1.

EXAMPLE 3 (a) Materials Same as in section a of Example 2, except that first the 2-amino-thiazole is dissolved in the acetone, and the solution is treated with 1 lb. Darco and filtered before charging into the reactor (this treatment removing insoluble matter and colored impurities from the 2-aminothiazole). The bis compound, separated by centrifuging, washed with water, and dried, is very light tan in color, melts .at 130 C., and weighs 124 lbs. (representing 99.0% of the theoretical yield).

(5) Materials I Pounds "Bis compound (dry) 124 38% hydrochloric acid 75 34% sodium hydroxide solution 135 Darco 5 Water 300 Procedure The water and hydrochloric acid are mixed and heated to 98 C., the bis compound is added over a period of 30 minutes, and the temperature is then maintained at 100-103? C. for 40 minutes. The Darco is then added, andthe batch is cooled to 55 C. and filtered through a rubber-covered filter press. The filtrate is cooled to C., and the pH adjusted to 6.5 by addition of the sodium hydroxide solution; and the precipitated crude sulfathiazole is separated and dried. The product is light tan in color, melts at 187-190 C., and weighs 50.5 lbs.'

On conversion of this crude sulfathiazole into sodium-sulfathiazole and reconversion to sulfathiazole as described in section" 0 of Example 1, pure sulfathiazole is obtained in a yield of 68% of the theoretical (based on the 2-amino-thiazole).

(b, alternative.) The bis compound formed I in section a, before isolation, is converted into sulfathiazole (and sulfanilamide) by the procedure described in sections b and 0" of Example 1.

EXAMPLE 4 v The bis compound obtained as described in section a of Example 1 (either unisolated, or isolated and purified as described in section a. of Example 2) is mixed with a dilute aqueous solution of sodium carbonate (3 mols sodium carbonate per mol bis compound), and .the mixture is heated at 40 C. for -2 hours. The mixture is then cooled to 0 C., and the precipi tate (acetyl-sulfanilic acid) is separated; and the mother'liquor is neutralized, and the resulting precipitate (N acetyl sulfathiazole) is separated, and deacetylated in the usual manner (e. g., by heating with aqueous sodium hydroxide solution). I

EXAIWPLE 5 (a) 65 g. anhydrous magnesium sulfate is dissolved in 150 ml. water, and a solution of 40 g. sodium hydroxide in ml. water is added thereto. The resulting heavy slurry (of magnesium hydroxide) is added to a solution of g. sodium chloride in 400 ml. water; a solution of 50 g. Z-amino-thiazole in 200 m1. acetone is added; and, while agitating vigorously, 282 g. wet pace'tamino-benzenesulfonyl chloride (containing 240 g. of the dry sulfonchloride) is added rapidly. The temperature rises to 40 C., and the pH remains constant at about 8.0. Agitation is 0011'. tinued for 2 hours, and the insoluble reaction product (bis compound) is filtered off and washed with 1 liter water.

(12) The bis" compound is mixed with ml. ammonia water and 400 ml. water. and the mixture is heated at 65 C. for 2 hours; and the reaction mixture is then treated as described in section b of Example 1, to isolate the N -acetylsulfanilamide and N -acetyl-sulfathiazole formed.

EXAMPLE 6 (a), A solution of 120 g. sodium chloride in 400 compound) is mixed with 150 m1. ammonia water, and the mixture is heated at 65 C. for 2 hours; and the reaction mixture is then treated as described in section b of Example 1, to isolate the N aoetyl-sulfanilamide and N -acetylsulfathiazole formed.

EXAMPLE 7 Materials Di-'(p-acetamino-benzenesulfonyl) derivative of Z-amino-thiazole (e. g., the crude bis compound obtained as described in section a of Example 2) -27.65 lbs.

Water1.5 gals.

Acc'tone10 gals.

Sodium hydroxide-5.6 lbs.

Guanidine hydrochloride-11.2 lbs.

Procedure The sodium hydroxide is dissolved in the water, in a reaction vessel equipped with an agita= tor, the solution is cooled to 68-'77 F., and the acetone is added. Then the guanidine hydrochloride is added in portions, while agitating the mixture and maintaining its temperature at 68-77 F. The mixture is agitated for minutes longer, and cooled to 32 F.; and, .while agitating, the bis compound is then added at such rate that the temperature is maintained at 32-40 F., and the agitation and temperature maintenance continued for 15 minutes beyond the addition. After the reaction mixture has stood at room tem perature for 2 hours, 100 gals. water is added, while agitating; and after several hours, the alkali-insoluble material (N -acetyl-sulfaguanidine) is filtered ofi.

The filter cake is washed with water (the wash being combined with the filtrate), and dried, yielding a crude N -acetyl-sulfaguanidine melting at 255-260 C. The N -acetyl-sulfaguanidine is then de-acetylated in the conventional manner, e. g., by the procedure described for the deacetylation of N -acetyl-sulfanilamide in section 12 of Example 1.

The combined alkaline filtrate and wash of the filter cake is adjusted to pH 4 by addition of concentrated hydrochloric acid, while agitating; and after the reaction mixture has stood for 12-16 hours, the sup'ernate is removed, and the precipitate is recovered by filtration, washed, and dried. The crude N -acetyl-sulfathiazole thus obtained melts at 255-257 C. It is deacetylated in the conventional manner, e. g., as described in section (3" of Example 1.

EXAMPLE 8- Materials Di;-(p-acetamino-benzesulfonyl) derivative of 2- amino-thiazole (e. g.,. the crude bis compound obtained as described in section a of Example 2)-49.4 g. Pyridine-100 cc. 2-amino-thiazolel0.1 g.

Procedure The 2-amino-thiazole' is dissolved in the pyridine; and, at room temperature, the bis compound is added to the solution in small portions,

while agitating. The temperature of the reaction thus obtained weighs 27 g. andmelts at 256- 257 C.' The filtrate (mother liquor) is then concentrated under reduced pressure, yielding a second crop weighing 13.5 g. and melting at-252-255" C. The combined crude N -acetyl-sulfathiazole is dissolved in dilute sodium hydroxide solution, treated with Darco, and filtered; and the filtrate is acidified with hydrochloric acid. The resulting precipitate is filtered ofi washed, and dried, yielding 38.5 g. of a purified N acety1-sulfathiazo1e melting at 258-260 C. p f

The N -acetyl-sulfathiazole is' deacetylated in the conventional manner, e. g., as described in section 0 of Example 1. [The unreacted 2- amino-thiazole can be recovered and'reusedJ Theinvention may be variously otherwise embodied within the scope of the appended claims.

I claim:

1. In the method of preparing sulfathiazole, the step of hydrolyzing a di-.(p-R-benzenesulfonyl) derivative of Z-amino-thiazole with an aqueous solution of a member of the group consisting of ammonia and guanidine, R representing a substituent capable of conversion into an amino group and selected from the class consisting of acylamino, nitro, azo and halo.

2. In the method of preparing sulfathiazole, the step of hydrolyzing a di-(p-acylamino-bentenesulionyl) derivative of 2-amino-thiazole with an aqueous solution of a member of the group consisting of ammonia and guanidine, cooling the reaction mixture, separating the'precipitated'pacylamino-benzene-sulfonamide, acidifying the filtrate, and recovering the precipitated N -acylsulfathiazole.

. 3. In the method of preparing. sulfathiazola the step of hydrolyzing the di- (p-acetaminoebenzenesulfonyl) derivative of 2-amino-thiazole by heating with aqueous ammonia, and separating the N -acetyl-sulfanilamide and N -acetyl-sulfathiazole formed.

4. In the method of preparing sulfathiazole, the step of hydrolyzing the di- (p-acetamino-benzenesulfonyl) derivative of 2-amino-thiazole by'heating with aqueous guanidine, and separating the N -acetyl-sulfaguanidine and N -acetyl s'ulfathie azole formed.

THOMAS F. CLEARY, Jr.

' REFERENCES orrnn The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,322,974 Salomon June 29, 1943 2,357,249 Anderson Aug. 29, 1944 2,386,852 Hartman et al Oct. 16, 1945 2,392,125 Dhein Jan. 1,1946 2,429,184 Hartman et al Oct. 14, I947 FOREIGN PATENTS ii umber Country Date 542,160 Great Britain Dec. 29, 1941 545,419 Great Britain May 26, 1942 219,143 Switzerland May 16, 1 942 229,080 Switzerland I Dec. 16, 1943 OTHER REFERENCES Ser. N0. 334,990, Foldi et al. (A. P. C), published April 20, 1943.

Raiziss et al.: J. Amer. Chem. Soc, vol. 63 (1941), pp. 3124-3136. 

1. IN THE METHOD OF PREPARING SULFATHIAZOLE, THE STEP OF HYDROLYZING A DI-(P-R-BENZENESULFONYL) DERIVATIVE OF 2-AMINO-THIAZOLE WITH AN AQUEOUS SOLUTION OF A MEMBER OF THE GROUP CONSISTING OF AMMONIA AND GUANIDINE, R REPRESENTING A SUBSTITUENT CAPABLE OF CONVERSION INTO AN AMINO GROUP AND SELECTED FROM THE CLASS CONSISTING OF ACYLAMINO, NITRO, AZO AND HALO. 